PROJECT SUMMARY/ABSTRACT Asthma is a chronic inflammatory lung disease that affects one in every twelve Americans. Most people with asthma experience type 2 lung inflammation triggered by the inhalation of allergens. This type 2 inflammation, characterized in part by Th2 cells and eosinophilia, represents an adaptive immune response to allergens. Recently, Th17 cell responses have also been described in asthma, especially in the most severe patients. As adaptive immunity is principally orchestrated by antigen presenting cells like dendritic cells (DCs), lung DCs are implicated as crucial players in the development of asthma. However, the molecular mechanisms of how DCs promote Th2 responses, as opposed to Th17 responses, remain controversial. Our group and others have identified IRF4 as a key transcription factor in lung DCs that initiate type 2 inflammation. We have found that two distinct allergens activate DCs to upregulate the transcription factor IRF4 and downstream cytokines IL-33 and IL-10. Critically, mice lacking IRF4 in DCs do not develop type 2 responses to HDM, suggesting that IRF4 is a key transcription factor in lung DCs that initiate type 2 inflammation. IRF4 is not required for DC uptake of allergen in the lung tissue at the site of allergen exposure. Further, IRF4 is not required for allergen- bearing DCs to reach the lung-draining lymph nodes (LLN). However, early T resident memory responses are impaired when DCs are deficient in IRF4. This suggests that IRF4 is required for DC-T cell interactions resulting in Th2 instruction or memory specification. My central hypothesis is that IRF4 is required in DCs during Th2 initiation via the actions of its downstream effector molecules such as IL-33 and IL-10 in the LLN. To address my hypothesis, I propose to determine 1) the mechanisms by which IRF4 expression by DCs regulates type 2 inflammation and the development of resident memory Th2 cells and 2) the role of downstream effectors of IRF4 expression in DCs in type 2 inflammation and memory responses. Understanding the mechanisms by which DCs promote inflammation during asthma is critical to the development of new therapeutic targets. IRF4, or its downstream effector molecules, are attractive candidates for this purpose since IRF4(+) DCs have been implicated in both Th2 and Th17 asthma phenotypes. Through the proposed study, we seek to reveal how these IRF4(+) DCs function to promote type 2 inflammation in mouse models of experimental asthma.